Current therapy for multiple myeloma is ineffective and nearly all patients will die of their disease at a median of three years following diagnosis. As observed in treatment of other lymphohematopoietic malignancies, high- dose therapy accompanied by autologous bone marrow or blood progenitor cell transplantation can improve disease control and perhaps extend survival. In order to improve available therapy for patients with multiple myeloma, in this proposal we will investigate: the effectiveness of high-dose therapy and autologous transplantation; biologically based techniques for enrichment of hematopoietic progenitor cell populations while depleting clonogenic myeloma cells; and the utility of sophisticated and sensitive minimal residual disease assays to evaluate and subsequently refine the therapeutic plan. because the drug sensitivity, proliferative response to Interleukin-6, cell surface phenotype and interactions with hematopoietic stroma differ between malignant myeloma cells and benign hematopoietic progenitor/stem cells, we propose to exploit these differences in order to improve treatments available for multiple myeloma. We propose therefore; 1) to characterize and quantify mobilized hematopoietic progenitors present in peripheral blood stem cell collections from myeloma patients and to develop and test methods for ex vivo stem cell selection and expansion in long-term culture, in order to have sufficient hematopoietic cells from engraftment and to deplete clonal myeloma cells through the selection and ex vivo culture; 2) to perform a series of clinical trials of high-dose therapy with autologous transplantation for treatment of multiple myeloma which will include retroviral marking of infused hematopoietic and/or tumor progenitors to allow tracking of the source of engraftment and relapse, and will include post-transplant immunotherapy with alpha-interferon and/or Interleukin-2: (3) to determine the relative precision of clonal tumor measurements within the mobilized stem cell populations and in the clinical evaluation of transplanted patients. We will compare the precision and sensitivity of conventional clinical measurements of disease burden, in vitro myeloma culture and allele-specific oligonucleotide-polymerase chain reaction. These laboratory studies will be used to design and to evaluate modifications in stem cell selection and expansion which will be directly tested in follow-up clinical trials designed to improve the therapeutic outcome for patients with multiple myeloma.